Each year a significant number of epilepsy patients present to the Yale Epilepsy Center with highly debilitating intractable epilepsy. When epilepsy is refractory to drug therapy, the best outcome occurs if the epileptogenic tissue is removed surgically. However, this approach to curing epilepsy is only effective if the epileptogenic tissue is limited in extent (focal) and identifiable. Many of these patients have no abnormalities visible on MR, PET, or SPECT scanning, or they have discordant findings across several measures, making localization of the epileptogenic tissue that generates the seizures difficult. This proposal is aimed at further developing and understanding combined electroencephalography and functional magnetic resonance imaging (EEG-fMRI). In this approach, EEG monitoring is performed during a functional MRI scanning session. A number of functional imaging approaches including, blood oxygenation level dependent (BOLD) contrast, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2)) will be investigated to identify local tissue regions that exhibit signal changes in synchrony with interictal epileptiform discharges (lEDs). The experiments are designed to improve our understanding of the relationship between MR measures of neuronal activity in the presence of epileptiform activity, and neuronal signatures of activity based on surface or depth recorded EEG. Characteristics of the measured response (peak integration, time-to-peak, amplitude, and duration) for specific tissues will be compared in an F-test with type of epilepsy and concordance with difference SPECT and intracranial recordings. In addition, the EEG-fMRI localization will be directly compared spatially, with the epileptogenic tissue localization obtained using difference SPECT imaging, and with the clinical gold standard of invasive recordings from intracranial implanted electrodes, and finally with surgical outcome. Little is currently known about the neurophysiological response to lEDs, the relationship between EEG and fMRI measures, nor of the relationship between this inter-ictal and ictal activity. The experiments proposed in this work will provide a better understanding of these issues at a basic neuroscience level, while also allowing validation through invasive monitoring. These developments will improve the efficacy of seizure localization, allow for more precise targeting of surgical interventions through better localization, and improve outcomes from surgery. A large epilepsy population exists that could benefit greatly from better mapping techniques and these techniques may ultimately replace invasive methods decreasing health care costs and morbidity.